{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T14:02:16Z","timestamp":1753884136404,"version":"3.41.2"},"reference-count":47,"publisher":"The Company of Biologists","issue":"10","license":[{"start":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T00:00:00Z","timestamp":1697500800000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["21H03148","22K21036","21K17159","20H03896","19KK0232","20K21673"],"award-info":[{"award-number":["21H03148","22K21036","21K17159","20H03896","19KK0232","20K21673"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004206","name":"Osaka University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004206","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,10,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Cleft palate has a multifactorial etiology. In palatal fusion, the contacting medial edge epithelium (MEE) forms the epithelial seam, which is subsequently removed with the reduction of p63. Failure in this process results in a cleft palate. We herein report the involvement of janus kinase 2 (JAK2)\/signal transducer and activator of transcription 3 (STAT3) signaling in palatal fusion and that folic acid rescues the fusing defect by reactivating JAK2\/STAT3. In closure of bilateral palatal shelves, STAT3 phosphorylation was activated at the fusing MEE and mesenchyme underlying the MEE. JAK2 inhibition by AG490 inhibited STAT3 phosphorylation and resulted in palatal fusion failure without removal of the epithelial seam, in which p63 and keratin 17 (K17) periderm markers were retained. Folic acid application restored STAT3 phosphorylation in AG490-treated palatal explants and rescued the fusion defect, in which the p63- and K17-positive epithelial seam were removed. The AG490-induced palatal defect was also rescued in p63 haploinsufficient explants. These findings suggest that JAK2\/STAT3 signaling is involved in palatal fusion by suppressing p63 expression in MEE and that folate restores the fusion defect by reactivating JAK2\/STAT3.<\/jats:p>","DOI":"10.1242\/dmm.050085","type":"journal-article","created":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T08:06:01Z","timestamp":1697529961000},"source":"Crossref","is-referenced-by-count":0,"title":["The roles of JAK2\/STAT3 signaling in fusion of the secondary palate"],"prefix":"10.1242","volume":"16","author":[{"given":"Naoki","family":"Yoshida","sequence":"first","affiliation":[{"name":"Department of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5303-4763","authenticated-orcid":false,"given":"Toshihiro","family":"Inubushi","sequence":"additional","affiliation":[{"name":"Department of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takumi","family":"Hirose","sequence":"additional","affiliation":[{"name":"Department of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gozo","family":"Aoyama","sequence":"additional","affiliation":[{"name":"Department of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Kurosaka","sequence":"additional","affiliation":[{"name":"Department of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4419-9643","authenticated-orcid":false,"given":"Takashi","family":"Yamashiro","sequence":"additional","affiliation":[{"name":"Department of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Osaka University, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2023,10,17]]},"reference":[{"key":"2023101708052858700_DMM050085C1","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1038\/nrc2657","article-title":"p21 in cancer: intricate networks and multiple activities","volume":"9","author":"Abbas","year":"2009","journal-title":"Nat. Rev. Cancer"},{"key":"2023101708052858700_DMM050085C2","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1111\/odi.14146","article-title":"Genetic and epigenetic studies in non-syndromic oral clefts","volume":"28","author":"Alade","year":"2022","journal-title":"Oral Dis."},{"key":"2023101708052858700_DMM050085C44","doi-asserted-by":"publisher","first-page":"2570","DOI":"10.1002\/ijc.29923","article-title":"Constitutive activation of STAT3 in breast cancer cells: A review","volume":"138","author":"Banerjee","year":"2016","journal-title":"Int. J. Cancer"},{"key":"2023101708052858700_DMM050085C3","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1242\/dev.067082","article-title":"Palatogenesis: morphogenetic and molecular mechanisms of secondary palate development","volume":"139","author":"Bush","year":"2012","journal-title":"Development"},{"key":"2023101708052858700_DMM050085C45","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1593\/neo.13706","article-title":"The IL-6\/JAK\/Stat3 feed-forward loop drives tumorigenesis and metastasis","volume":"15","author":"Chang","year":"2013","journal-title":"Neoplasia"},{"key":"2023101708052858700_DMM050085C4","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1242\/dev.00907","article-title":"Death is the major fate of medial edge epithelial cells and the cause of basal lamina degradation during palatogenesis","volume":"131","author":"Cuervo","year":"2004","journal-title":"Development"},{"key":"2023101708052858700_DMM050085C5","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/j.ydbio.2004.10.023","article-title":"Overexpression of Smad2 in Tgf-beta3-null mutant mice rescues cleft palate","volume":"278","author":"Cui","year":"2005","journal-title":"Dev. Biol."},{"key":"2023101708052858700_DMM050085C6","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.1101\/gad.311852.118","article-title":"STAT3 is a master regulator of epithelial identity and KRAS-driven tumorigenesis","volume":"32","author":"D'Amico","year":"2018","journal-title":"Genes Dev."},{"key":"2023101708052858700_DMM050085C7","doi-asserted-by":"publisher","first-page":"CD007950","DOI":"10.1002\/14651858.CD007950.pub3","article-title":"Effects and safety of periconceptional oral folate supplementation for preventing birth defects","volume":"2015","author":"De-Regil","year":"2015","journal-title":"Cochrane Database Syst. Rev."},{"key":"2023101708052858700_DMM050085C8","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1002\/aja.1001500308","article-title":"Fusion of nasal swellings in the mouse embryo: regression of the nasal fin","volume":"150","author":"Gaare","year":"1977","journal-title":"Am. J. Anat."},{"key":"2023101708052858700_DMM050085C46","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1146\/annurev-neuro-062012-170354","article-title":"Neural tube defects","volume":"37","author":"Greene","year":"2014","journal-title":"Annu. Rev. Neurosci."},{"key":"2023101708052858700_DMM050085C9","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1056\/NEJM199903043400904","article-title":"Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder","volume":"340","author":"Grimbacher","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"2023101708052858700_DMM050085C10","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.ydbio.2006.07.042","article-title":"Molecular control of secondary palate development","volume":"301","author":"Gritli-Linde","year":"2007","journal-title":"Dev. Biol."},{"key":"2023101708052858700_DMM050085C11","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/S0070-2153(08)00602-9","article-title":"The etiopathogenesis of cleft lip and cleft palate: usefulness and caveats of mouse models","volume":"84","author":"Gritli-Linde","year":"2008","journal-title":"Curr. Top. Dev. Biol."},{"key":"2023101708052858700_DMM050085C12","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.1016\/j.cellsig.2015.03.020","article-title":"Folic acid mediates activation of the pro-oncogene STAT3 via the Folate Receptor alpha","volume":"27","author":"Hansen","year":"2015","journal-title":"Cell. Signal."},{"key":"2023101708052858700_DMM050085C13","doi-asserted-by":"publisher","first-page":"1212","DOI":"10.1002\/jcp.24856","article-title":"TGF\u03b23 regulates periderm removal through \u0394Np63 in the developing palate","volume":"230","author":"Hu","year":"2015","journal-title":"J. Cell. Physiol."},{"key":"2023101708052858700_DMM050085C14","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1038\/s41392-021-00791-1","article-title":"The JAK\/STAT signaling pathway: from bench to clinic","volume":"6","author":"Hu","year":"2021","journal-title":"Signal Transduct. Target Ther."},{"key":"2023101708052858700_DMM050085C15","doi-asserted-by":"publisher","first-page":"28012","DOI":"10.1038\/srep28012","article-title":"IL-6 mediates differentiation disorder during spermatogenesis in obesity-associated inflammation by affecting the expression of Zfp637 through the SOCS3\/STAT3 pathway","volume":"6","author":"Huang","year":"2016","journal-title":"Sci. Rep."},{"key":"2023101708052858700_DMM050085C16","doi-asserted-by":"publisher","first-page":"dmm049093","DOI":"10.1242\/dmm.049093","article-title":"Ras signaling and RREB1 are required for the dissociation of medial edge epithelial cells in murine palatogenesis","volume":"15","author":"Inubushi","year":"2022","journal-title":"Dis. Model. Mech."},{"key":"2023101708052858700_DMM050085C17","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.1242\/dev.089615","article-title":"Smad4-Irf6 genetic interaction and TGF\u03b2-mediated IRF6 signaling cascade are crucial for palatal fusion in mice","volume":"140","author":"Iwata","year":"2013","journal-title":"Development"},{"key":"2023101708052858700_DMM050085C18","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1002\/ajmg.c.31380","article-title":"Modeling anterior development in mice: diet as modulator of risk for neural tube defects","volume":"163C","author":"Kappen","year":"2013","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"2023101708052858700_DMM050085C19","doi-asserted-by":"publisher","first-page":"242","DOI":"10.4161\/org.7.4.17926","article-title":"Palatogenesis: engineering, pathways and pathologies","volume":"7","author":"Levi","year":"2011","journal-title":"Organogenesis"},{"key":"2023101708052858700_DMM050085C20","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1172\/JCI37964","article-title":"Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3\/p63\/Jagged\/Notch cascade","volume":"120","author":"Ma","year":"2010","journal-title":"J. Clin. Invest."},{"key":"2023101708052858700_DMM050085C21","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1083\/jcb.143.2.469","article-title":"Onset of keratin 17 expression coincides with the definition of major epithelial lineages during skin development","volume":"143","author":"Mcgowan","year":"1998","journal-title":"J. Cell Biol."},{"key":"2023101708052858700_DMM050085C41","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/8773","article-title":"Epidermal growth factor receptor function is necessary for normal craniofacial development and palate closure","volume":"22","author":"Miettinen","year":"1999","journal-title":"Nat. Genet."},{"key":"2023101708052858700_DMM050085C22","doi-asserted-by":"publisher","first-page":"1676","DOI":"10.1172\/JCI200422154","article-title":"Cleft palate: players, pathways, and pursuits","volume":"113","author":"Murray","year":"2004","journal-title":"J. Clin. Invest."},{"key":"2023101708052858700_DMM050085C23","doi-asserted-by":"publisher","first-page":"4167","DOI":"10.1096\/fj.10-165084","article-title":"Folic acid in early pregnancy: a public health success story","volume":"24","author":"Obican","year":"2010","journal-title":"FASEB J."},{"key":"2023101708052858700_DMM050085C24","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1186\/1471-2164-14-113","article-title":"Systematic analysis of palatal transcriptome to identify cleft palate genes within TGF\u03b23-knockout mice alleles: RNA-Seq analysis of TGF\u03b23 Mice","volume":"14","author":"Ozturk","year":"2013","journal-title":"BMC Genomics"},{"key":"2023101708052858700_DMM050085C42","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1038\/ng1295-409","article-title":"Transforming growth factor-beta 3 is required for secondary palate fusion","volume":"11","author":"Proetzel","year":"1995","journal-title":"Nat. Genet."},{"key":"2023101708052858700_DMM050085C43","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1186\/s13046-019-1206-z","article-title":"STAT3 as a potential therapeutic target in triple negative breast cancer: a systematic review","volume":"38","author":"Qin","year":"2019","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"2023101708052858700_DMM050085C25","doi-asserted-by":"publisher","first-page":"3891","DOI":"10.1172\/JCI71946","article-title":"Periderm prevents pathological epithelial adhesions during embryogenesis","volume":"124","author":"Richardson","year":"2014","journal-title":"J. Clin. Invest."},{"key":"2023101708052858700_DMM050085C26","doi-asserted-by":"publisher","first-page":"e1006828","DOI":"10.1371\/journal.pgen.1006828","article-title":"p63 exerts spatio-temporal control of palatal epithelial cell fate to prevent cleft palate","volume":"13","author":"Richardson","year":"2017","journal-title":"PLoS Genet."},{"key":"2023101708052858700_DMM050085C27","doi-asserted-by":"publisher","first-page":"11208","DOI":"10.1038\/s41598-018-29681-3","article-title":"Runx1-Stat3-Tgfb3 signaling network regulating the anterior palatal development","volume":"8","author":"Sarper","year":"2018","journal-title":"Sci. Rep."},{"key":"2023101708052858700_DMM050085C28","doi-asserted-by":"publisher","first-page":"dmm038851","DOI":"10.1242\/dmm.038851","article-title":"Anterior cleft palate due to Cbfb deficiency and its rescue by folic acid","volume":"12","author":"Sarper","year":"2019","journal-title":"Dis. Model. Mech."},{"key":"2023101708052858700_DMM050085C29","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1002\/bdr2.1666","article-title":"Gestational exposure to valproic acid upregulates total Stat3 protein expression while downregulating phosphorylated Stat3 in CD-1 mouse embryos with neural tube defects","volume":"112","author":"Shafique","year":"2020","journal-title":"Birth Defects Res."},{"key":"2023101708052858700_DMM050085C30","doi-asserted-by":"publisher","first-page":"5419","DOI":"10.1038\/sj.onc.1203947","article-title":"Induction of p21WAF1\/CIP1 and cyclin D1 expression by the Src oncoprotein in mouse fibroblasts: role of activated STAT3 signaling","volume":"19","author":"Sinibaldi","year":"2000","journal-title":"Oncogene"},{"key":"2023101708052858700_DMM050085C31","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1387\/ijdb.041840tt","article-title":"Terminal differentiation of palatal medial edge epithelial cells in vitro is not necessarily dependent on palatal shelf contact and midline epithelial seam formation","volume":"48","author":"Takigawa","year":"2004","journal-title":"Int. J. Dev. Biol."},{"key":"2023101708052858700_DMM050085C32","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1016\/j.ydbio.2008.06.030","article-title":"Facial clefting in Tp63 deficient mice results from altered Bmp4, Fgf8 and Shh signaling","volume":"321","author":"Thomason","year":"2008","journal-title":"Dev. Biol."},{"key":"2023101708052858700_DMM050085C33","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1002\/tera.1420010106","article-title":"Pathogenesis of cleft lip and its relation to embryonic face shape in A-J and C57BL mice","volume":"1","author":"Trasler","year":"1968","journal-title":"Teratology"},{"key":"2023101708052858700_DMM050085C34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1086\/341450","article-title":"Splitting p63","volume":"71","author":"van Bokhoven","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"2023101708052858700_DMM050085C35","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1097\/GIM.0b013e3181833793","article-title":"Candidate gene\/loci studies in cleft lip\/palate and dental anomalies finds novel susceptibility genes for clefts","volume":"10","author":"Vieira","year":"2008","journal-title":"Genet. Med."},{"key":"2023101708052858700_DMM050085C36","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1111\/j.1601-0825.2009.01587.x","article-title":"Folic acid and orofacial clefts: a review of the evidence","volume":"16","author":"Wehby","year":"2010","journal-title":"Oral Dis."},{"key":"2023101708052858700_DMM050085C37","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1089\/scd.2016.0091","article-title":"Folic Acid Supports Pluripotency and Reprogramming by Regulating LIF\/STAT3 and MAPK\/ERK Signaling","volume":"26","author":"Wei","year":"2017","journal-title":"Stem Cells Dev."},{"key":"2023101708052858700_DMM050085C47","doi-asserted-by":"publisher","first-page":"5819","DOI":"10.1074\/jbc.M111.295964","article-title":"Roles of STAT3 and ZEB1 proteins in E-cadherin down-regulation and human colorectal cancer epithelial-mesenchymal transition","volume":"287","author":"Xiong","year":"2012","journal-title":"J. Biol. Chem."},{"key":"2023101708052858700_DMM050085C38","doi-asserted-by":"publisher","first-page":"538835","DOI":"10.3389\/fphys.2020.538835","article-title":"Observation of the epithelial cell behavior in the nasal septum during primary palate closure in mice","volume":"11","author":"Yamamoto","year":"2020","journal-title":"Front. Physiol."},{"key":"2023101708052858700_DMM050085C39","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/ng0501-29","article-title":"SOCS-1, a negative regulator of the JAK\/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity","volume":"28","author":"Yoshikawa","year":"2001","journal-title":"Nat. Genet."},{"key":"2023101708052858700_DMM050085C40","doi-asserted-by":"publisher","first-page":"1699","DOI":"10.1002\/bdr2.1827","article-title":"Folate intake, markers of folate status and oral clefts: an updated set of systematic reviews and meta-analyses","volume":"112","author":"Zhou","year":"2020","journal-title":"Birth Defects Res."}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.050085\/3232776\/dmm050085.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.050085\/3232776\/dmm050085.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T08:06:04Z","timestamp":1697529964000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/16\/10\/dmm050085\/333518\/The-roles-of-JAK2-STAT3-signaling-in-fusion-of-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,1]]},"references-count":47,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2023,10,1]]}},"URL":"https:\/\/doi.org\/10.1242\/dmm.050085","relation":{},"ISSN":["1754-8403","1754-8411"],"issn-type":[{"type":"print","value":"1754-8403"},{"type":"electronic","value":"1754-8411"}],"subject":[],"published":{"date-parts":[[2023,10,1]]},"article-number":"dmm050085"}}